Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention is in the field of medicine, particularly in the treatment of Type 2 diabetes and obesity. More specifically, the present invention relates to ⁇ 3 adrenergic receptor agonists useful in the treatment of Type 2 diabetes and obesity.
• Type 2 diabetes non-insulin dependent diabetes as well as obesity
• Patient compliance is usually poor.
• the problem is compounded by the fact that there are currently no approved medications that adequately treat either Type 2 diabetes or obesity.
• the ⁇ 3 receptor which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the ⁇ 1 and ⁇ 2 receptor subtypes yet is considerably less abundant. Stimulation of the ⁇ 1 and ⁇ 2 receptors can cause adverse effects such as tachycardia, arrhythmia, or tremors.
• An agonist that is selective for the ⁇ 3 receptor over the ⁇ 1 and ⁇ 2 receptors is, therefore, more desirable for treating Type 2 diabetes or obesity relative to a non-selective agonist.
• the present invention relates to a compound of formula I:
• the dashed line represents a single or double bond
• n 0, 1 or 2;
• a 1 , A 2 and A 3 are carbon or nitrogen provided that only one of A 1 , A 2 and A 3 can be nitrogen;
• D is NR 8 , O or S
• Het is an optionally substituted, optionally benzofused 5 or 6 membered heterocyclic ring
• R 1 and R 2 are independently H, halo, hydroxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 1 –C 4 haloalkyl, or SO 2 (C 1 –C 6 alkyl);
• R 3 is H or C 1 –C 6 alkyl
• R 4 forms a bond with X 2 or is H, cyano, C 1 –C 6 alkyl, CONR 9 R 9 or CO 2 R 9 ;
• R 5 forms a bond with X 2 or is H or C 1 –C 6 alkyl
• R 6 is independently at each occurrence halo, hydroxy, cyano, C 1 –C 6 alkyl, C 1 –C 4 haloalkyl or C 1 –C 6 alkoxy;
• R 7 is H, CO 2 R 10 , CONR 10 R 10 , CH ⁇ CHR 11 , CH 2 CH 2 R 11 , NR 10 R 10 , NR 10 SO 2 R 10 , O(CR 12 R 13 ) n R 14 , O(CR 12 R 13 ) p R 15 , SO 2 R 10 , SO 2 NR 10 R 10 , optionally substituted phenyl or optionally substituted heterocycle;
• R 8 forms a bond with X 2 or is H or C 1 –C 6 alkyl
• R 9 and R 10 are independently at each occurrence H, C 1 –C 6 alkyl or phenyl; or when two R 9 or two R 10 moieties are connected to the same nitrogen atom, then said R 9 or R 10 moieties may combine with the nitrogen to which they are attached to form a pyrollidinyl, piperidinyl or hexamethyleneimino ring;
• R 11 is cyano, CO 2 R 16 , CONR 16 R 16 , CONR 16 SO 2 R 16 , SO 2 R 16 , heterocycle or optionally substituted phenyl;
• R 12 and R 13 are independently at each occurrence H or C 1 –C 6 alkyl
• R 14 is hydrogen, CO 2 R 17 , CONR 17 R 17 , SO 2 R 17 , SO 2 NR 17 R 17 , optionally substituted phenyl or optionally substituted heterocycle,
• R 15 is cyano, NR 18 R 18 , NR 18 SO 2 R 18 or OR 18 ;
• R 16 , R 17 and R 18 are independently at each occurrence H, C 1 –C 6 alkyl or phenyl; or when two R 16 or two R 17 or two R 18 moieties are connected to the same nitrogen atom, then said R 16 or R 17 or R 18 moieties may combine with the nitrogen to which they are attached to form a pyrollidinyl, piperidinyl or hexamethyleneimino ring;
• n 0, 1, 2 or 3;
• p 1, 2 or 3;
• X is absent or is OCH 2 or SCH 2 ;
• X 1 is absent or is (CR 19 R 20 ) q ;
• X 2 is absent or is CO, CONR 21 or NR 21 CO;
• q 1, 2, 3, 4 or 5;
• R 19 and R 20 are independently at each occurrence H or C 1 –C 6 alkyl; or R 19 and R 20 combine with the carbon to which they are both attached to form a C 3 –C 7 carbocyclic ring; and
• R 21 is H or C 1 –C 6 alkyl; or a pharmaceutical salt thereof.
• the present invention also relates to processes for preparing, as well as novel pharmaceutical formulations containing, a compound of formula I.
• the pharmaceutical formulations of the present invention may be adapted for use in treating Type 2 diabetes and obesity and for agonizing the ⁇ 3 receptor.
• the present invention also relates to methods for treating Type 2 diabetes and obesity, as well as a method for agonizing the ⁇ 3 receptor employing a compound of formula I.
• the present invention relates to a compound of formula I for use in treating Type 2 diabetes and obesity as well as a compound of formula I for use in agonizing the ⁇ 3 receptor.
• the present invention is further related to the use of a compound of formula I for the manufacture of a medicament for treating Type 2 diabetes and obesity as a well as for agonizing the ⁇ 3 receptor.
• halo represents fluoro, chloro, bromo, or iodo.
• C 1 –C 6 alkyl represents a straight, branched or cyclic hydrocarbon moiety having from one to six carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl and the like.
• C 1 –C 4 alkyl refers specifically to methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and cyclobutyl.
• a “C 1 –C 4 haloalkyl” group is a C 1 –C 4 alkyl moiety substituted with up to six halo atoms, preferably one to three halo atoms. An example of a haloalkyl group is trifluoromethyl.
• a “C 1 –C 6 alkoxy” group is a C 1 –C 6 alkyl moiety connected through an oxy linkage.
• optionally substituted means an optional substitution of one to three, preferably one or two groups independently selected from halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, triazole, tetrazole, 4,5-dihydrothiazole, C 1 –C 6 alkyl, C 1 –C 4 haloalkyl, C 1 –C 6 alkoxy, COR 22 , CONR 22 R 22 , CO 2 R 22 , NR 22 R 22 , NR 22 COR 23 , NR 22 SO 2 R 23 , OCOR 23 , OCO 2 R 22 , OCONR 22 R 22 , SR 22 , SOR 23 , SO 2 R 23 and SO 2 (NR 22 R 22 ), where R 22 is independently at each occurrence H, C 1 –C 6 alkyl, phenyl or benzyl and R 23 is independently at each occurrence C 1 –C 6 alkyl, phenyl or
• heterocycle and “heterocyclic” represent a stable, saturated, partially unsaturated, fully unsaturated or aromatic 5 or 6 membered ring, said ring having from one to four heteroatoms that are independently selected from the group consisting of sulfur, oxygen, and nitrogen.
• the heterocycle may be attached at any point which affords a stable structure.
• heterocycles include 1,3-dioxolane, 4,5-dihydrooxazole, furan, imidazole, imidazolidine, isothiazole, isoxazole, morpholine, oxadiazole, oxazole, oxazolidinedione, oxazolidone, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrazole, thiadiazole, thiazole, thiophene and triazole.
• benzofused heterocycles include benzoxazole, benzimidazole, benzofuran, benzothiophene, benzothiazole, azaindole, and indole. Further specific examples of benzofused and non-benzofused heterocycles are described below in the Preparations and Examples sections.
• suitable solvent refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.
• the term “patient” includes human and non-human animals such as companion animals (dogs and cats and the like) and livestock animals.
• Livestock animals are animals raised for food production. Ruminants or “cud-chewing” animals such as cows, bulls, heifers, steers, sheep, buffalo, bison, goats and antelopes are examples of livestock.
• Other examples of livestock include pigs and avians (poultry) such as chickens, ducks, turkeys and geese.
• livestock include fish, shellfish and crustaceans raised in aquaculture.
• exotic animals used in food production such as alligators, water buffalo and ratites (e.g., emu, rheas or ostriches).
• the preferred patient of treatment is a human.
• treating and “treat”, as used herein, include their generally accepted meanings, i.e., preventing, prohibiting, restraining, alleviating, ameliorating, slowing, stopping, or reversing the progression or severity of a pathological condition, or sequela thereof, described herein.
• preventing means that the recipient of a compound of formula I will incur or develop any of the pathological conditions, or sequela thereof, described herein.
• the term “effective amount” means an amount of a compound of formula I that is capable of treating conditions, or detrimental effects thereof, described herein or that is capable of agonizing the ⁇ 3 receptor.
• selective ⁇ 3 receptor agonist means a compound that displays preferential agonism of the ⁇ 3 receptor over agonism of the ⁇ 1 or ⁇ 2 receptor.
• ⁇ 3 selective compounds behave as agonists for the ⁇ 3 receptor at lower concentrations than that required for similar agonism at the ⁇ 1 and ⁇ 2 receptors.
• a ⁇ 3 selective compound also includes compounds that behave as agonists for the ⁇ 3 receptor and as antagonists for the ⁇ 1 and ⁇ 2 receptors.
• pharmaceutical when used herein as an adjective means substantially non-deleterious to the recipient patient.
• formulation is intended to encompass a product comprising the active ingredient(s) (compound of formula I), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
• the pharmaceutical formulations of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical carrier.
• unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other non-human animals (as described above), each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
• the compound of formula I may exist as a pharmaceutical base addition salt thereof.
• Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like.
• the compound of formula I can also exist as a pharmaceutical acid addition salt.
• Such salts include the salicylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-1,4 dioate, 3-hexyne-2,5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate,
• Certain compounds of the invention are particularly interesting and are preferred.
• a 1 , A 2 and A 3 are carbon
• Het is an optionally substituted 5-membered, non-benzofused ring
• Het is selected from benzothiophene; furan; isoxazole; oxazole; pyrrole; tetrazole and thiophene; wherein said Het moieties are optionally substituted once with methyl, cyano, SO 2 NH 2 or COCH 3 ;
• Het is thien-2-yl optionally substituted once with methyl, cyano, SO 2 NH 2 or COCH 3 ;
• Het is thien-2-yl optionally substituted once with cyano, SO 2 NH 2 or COCH 3 ;
• R 1 is H, methyl, ethyl, CF 3 , chloro or fluoro;
• R 1 is H, methyl, chloro or fluoro
• R 1 is H or fluoro
• R 1 is H
• R 2 is H, methyl, ethyl, CF 3 , chloro or fluoro;
• R 2 is H, methyl, chloro or fluoro
• R 2 is H or fluoro
• R 2 is H
• R 5 forms a bond with X 2 ;
• R 6 is cyano at each occurrence
• R 7 is at the 6- or 7-position of the indole, benzofuran or benzothiophene ring system to which it is attached;
• R 7 is at the 7-position
• R 7 is H or CO 2 H
• R 7 is CH ⁇ CHR 11 ;
• R 11 is tetrazole, CONR 16 R 16 or CO 2 R 16 ; and
• R 16 is independently H or C 1 –C 4 alkyl at each occurrence;
• R 7 is CH 2 CH 2 R 11 , R 11 is CO 2 R 16 or CONR 16 R 16 , and R 16 is independently H or C 1 –C 4 alkyl at each occurrence;
• R 7 is CH 2 CH 2 R 11 , R 11 is 1,2,3,4-tetrazole or phenyl substituted once with SO 2 NR 22 R 22 , and R 22 is independently H or C 1 –C 4 alkyl at each occurrence;
• R 7 is thienyl substituted once with CO 2 H or phenyl substituted once with CO 2 H;
• R 7 is OCH 2 CONHSO 2 (C 1 –C 4 alkyl); OCH 2 CH 2 NHSO 2 (C 1 –C 4 alkyl); OCH 2 CN; OCH 2 CO 2 R 17 ; OCH 2 CONR 18 R 18 ; O(pyridine) wherein said pyridine moieity is substituted once with cyano or CO 2 H; OCH 2 (tetrazole) or OCH 2 (4,5-dihydrothiazole), and R 17 and R 18 are independently H or C 1 –C 4 alkyl at each occurrence;
• R 7 is NHSO 2 R 10 and R 10 is C 1 –C 4 alkyl or phenyl;
• R 7 is CH ⁇ CHR 11 ;
• R 11 is tetrazole or CO 2 H;
• R 7 is CH 2 CH 2 R 11 and R 11 is 1,2,3,4-tetrazole;
• R 7 is OCH 2 CN; OCH 2 CO 2 H; or OCH 2 (tetrazole);
• R 8 is H
• X is OCH 2 and is connected through the 4-position of the indole ring (as shown in all of the exemplified compounds herein);
• X 1 is (CR 19 R 20 ) q where R 19 and R 20 are independently H or methyl at each occurrence and q is 2;
• X 1 is C(CH 3 ) 2 CH 2 ;
• the compound of formula I is the glycolate salt.
• the compound of formula I may be prepared as described in the following Schemes and Examples.
• the reaction of Scheme 1 may be carried out under conditions appreciated in the art for the amination of epoxides.
• the epoxide of formula II may be combined with an amine of formula III in a lower alcohol, dimethylformamide, dimethylsulfoxide, or acetone, preferably ethanol, isopropanol, n-butanol or t-butanol, at room temperature to the reflux temperature of the reaction mixture, preferably between 40° C.–90° C.
• the reaction may also be carried out under conditions generally described in Atkins, et al., Tet. Let ., 27:2451, 1986.
• These conditions include mixing the reagents in the presence of trimethylsilyl acetamide in a polar aprotic solvent such as acetonitrile, dimethylformamide, acetone, dimethylsulfoxide, dioxane, diethylene glycol dimethyl ether, tetrahydrofuran, or other polar aprotic solvents in which the reagents are soluble.
• a polar aprotic solvent such as acetonitrile, dimethylformamide, acetone, dimethylsulfoxide, dioxane, diethylene glycol dimethyl ether, tetrahydrofuran, or other polar aprotic solvents in which the reagents are soluble.
• the compound of formula I may also be prepared via a Suzuki coupling reaction as shown in Scheme 2.
• a compound of formula IV may be reacted with a compound of formula III as described above in Scheme 1.
• the compound of formula V (an aryl halide) may then be reacted with a heteroaryl boronic acid, an aryl boronic ester, or an aryl boronic cyclic ester, preferably an aryl boronic acid, under conditions appreciated in the art for the coupling of aromatic halides with aryl boronic acids and their derivatives.
• This coupling is known in the art generally as a Suzuki coupling.
• an aryl triflate may also be employed in the present Suzuki coupling as an alternative to employing an aryl halide.
• epoxide starting materials employed in Schemes 1 and 2 may be prepared by techniques recognized and appreciated by one skilled in the art. See, e.g., U.S. Pat. No. 4,663,334; European Patent Application 171209; Korn, et al., J. Pharm. Sci ., 69(9):1010–13, 1980 and references cited below in the Preparations section for representative and/or analogous procedures for preparing the epoxides of formula II and IV.
• epoxides of formula II, where X is OCH 2 or SCH 2 may be prepared according to the procedure detailed in Scheme 3 wherein R 19 is OH or SH and X′ is OCH 2 or SCH 2 .
• amines of formula III employed in Scheme 1 may also be prepared by techniques recognized and appreciated by one skilled in the art. See, e.g., the Preparations below or the references cited therein for representative and/or analogous procedures for preparing the amines of formula III.
• Epoxides 1–21 and 23–30 are prepared as described below for use as described in Scheme 1.
• Epoxide 22 and 31 are prepared as described below for use as described in Scheme 2. These epoxides are pictured below in Table 1.
• Epoxide 12 is prepared from 2-methoxyphenylboronic acid and 2-bromo-5-fluorothiophene; by a procedure substantially similar to that described for Epoxide 30.
• the protected product from above is demethylated with pyridine hydrochloride neat at 200 degrees for 3 hours.
• the reaction is poured into ice/water and ethyl acetate is added.
• the layers are separated and the organic layer is washed with water, dried over sodium sulfate and concentrated.
• the resulting residue is flash chromatographed with ethyl acetate/hexanes to afford 3-hydroxy-2-(thien-2-yl)pyridine (77%).
• 3-Hydroxy-2-(thien-2-yl)pyridine is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
• Epoxide 14 is prepared from 2-(3-methylisoxazol-5-yl)phenol ( J. Org. Chem. 49:4419, 1984) and (2S)-glycidyl 3-nitrobenzenesulfonate by a procedure substantially similar to that described for Epoxide 1.
• Epoxides 16–20 are prepared by a procedure substantially similar to that described for Epoxide 15.
• the starting halogeno thiophenes used to prepare Epoxides 15–20 are known from the literature, see e.g., J. Mater. Chem ., 5(4), 653–61, 1995; J. Chem. Soc ., Perkin Trans. 2, 5:625–30, 1982; Chem. Scr ., 5(5), 217–26, 1974; Bull. Soc. Chim. Fr ., 11:4115–20, 1967; Bull. Soc. Chim. Fr ., 11:4121–6, 1967; Bull. Inst. Chem. Res ., 52(3):561–5, 1974; J. Med. Chem ., 43(16):3168–3185, 2000; Bioorg. Med. Chem. Lett., 10(5):415–418, 2000; and JP 08311060.
• 2-Thienyl-1-methoxybenzene (10 g, 53 mmol) is cooled to ⁇ 78° C. in dry tetrahydrofuran (265 ml) under nitrogen while stirring.
• n-Butyl lithium in hexanes (1.6M, 37 ml, 59 mmol, 1.1 eq.) is added slowly and the resulting mixture is stirred cold for an hour.
• Chloromethyl formate (4.1 ml, 53 mmol, 1.0 eq.) is added and the reaction is stirred cold for another hour. The mixture is allowed to warm to room temperature before quenching with saturated bicarbonate solution and ethyl acetate.
• epoxide (4.44 g, 86%) is prepared from 2-fluoro-6-iodophenol and (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 except using butanone as solvent.
• 2-(Tetrazol-3-yl)phenol (32.8 g, 202.3 mmol) is dissolved in dimethylformamide (100 mL) and water (25 mL) and cooled in ice.
• Sodium hydroxide (8.49 g, 212.3 mmol) in water (20 mL) is added and the solution is warmed to ambient temperature. After thirty minutes, iodomethane (31.58 g, 222.5 mmol) is added neat. The solution is stirred for 15 hours then diluted with ethyl acetate (300 mL) and water (500 mL).
• the aqueous layer is washed three times with ethyl acetate (300 mL) and the organic layers are combined, washed three times with water (1 L), once with brine (1.2 L), dried over magnesium sulfate, filtered and concentrated in vacuo.
• the solid is purified by flash column chromatography (80% hexane:20% ethyl acetate gradient to 50% hexane:50% ethyl acetate as an eluent) to give 23.5 g of 2-(1-methyltetrazol-3-yl)phenol (66%).
• the reaction is cooled, diluted with ethyl acetate, washed with brine, and the brine back extracted with ethyl acetate.
• the extracts are combined, washed with aqueous NaHCO 3 , brine, dried (Na 2 SO 4 ), filtered, and the filtrate is concentrated.
• the residue is purified by chromatography (SiO 2 , ethyl acetate/hexane gradient) to give 943 mg (70%) of 5-(2-methoxyphenyl)thiophene-2-sulfonamide.
• Amines 1–88 are prepared as described below or are obtained from commercial sources for use as described in Schemes 1 or 2. These amines are pictured below in Table 2.
• Solid di-tert-butyl dicarbonate (20 g, 92 mmol) is added to a slurry of 2-methyl-1-[7-(benzyloxy)indol-3-yl]prop-2-ylamine (31.54 g, 107.1 mmol), triethylamine (16.5 mL, 118 mmol) and CH 2 Cl 2 (300 mL) at ambient temperature; within 2 hours the slurry became a homogeneous solution. After 23.5 hours, the solution is poured into water (200 mL), and the layers are separated. The organic layer is extracted with 0.5 M NaHSO 4 (200 mL), and the combined aqueous layers are rinsed with CH 2 Cl 2 (125 mL).
• trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (262 mg, 0.600 mmol) in dimethylformamide (3.5 mL) is added triethylamine (0.11 mL, 0.780 mmol), tetrakis(triphenylphosphine)-palladium (28 mg, 0.0240 mmol) and 2,4-bistrifluoromethylbenzeneboronic acid (201 mg, 0.780 mmol).
• the mixture is heated to 100° C. for 20 hours, then cooled, diluted with brine and ethyl acetate.
• the title amine is prepared from ⁇ 2-[7-(2,4-Bis-trifluoromethyl-phenyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl ⁇ -carbamic acid tert-butyl ester as described above for Amine 1 (208 mg, 100%).
• FDMS m/e 401 (M + +1).
• Phosphorous oxychloride (252 mL, 2.7 mol) is added dropwise over 15 minutes to precooled dimethylformamide ( ⁇ 10° C.) (1800 mL) while maintaining the temperature below ⁇ 5° C. and the resulting solution is stirred for 1 hour at ⁇ 10 to 0° C.
• a solution of 7-benzyloxyindole (502 g, 2.25 mmol) in dimethylformamide (900 mL) is added dropwise while maintaining the temperature below 0° C. The cooling is removed and the resulting mixture is allowed to warm to room temperature and stir for 1 hour. After cooling to 0° C., 5 N NaOH (4.5 L) is added over 20 minutes at 0° C. to 5° C.
• Lithium aluminum hydride (LAH, 24 g, 600 mmol) is added portionwise to dry tetrahydrofuran (1800 mL) at ⁇ 5° C. to 5° C.
• a solution of the nitroolefin from above (61.6 g, 200 mmol) in tetrahydrofuran (1200 mL) is added to the LAH solution over 30 minutes while maintaining the temperature at ⁇ 5° C. to 5° C.
• the reaction mixture is allowed to warm to 30° C. over 1.5 hours and is stirred at 25° C. to 35° C. for 2 hours. To complete the reaction, the mixture is heated to 60° C. for 30 minutes.
• the crude product is purified by silica gel chromatography (500 g silica gel) eluting with dichloromethane followed by 5% ethyl acetate/dichloromethane. Crystallization of the product containing fractions from ethyl acetate/hexanes affords 33.9 g (86% yield) of ⁇ 1-methyl-2-[7-(benzyloxy)-1H-indol-3-yl]ethyl ⁇ -carbamic acid tert-butyl ester.
• the crude product is purified by flash chromatography (500 g silica gel, eluted with 8 ⁇ 500 mL dichloromethane, 4 ⁇ 500 mL 5% ethyl acetate/dichloromethane, 6 ⁇ 500 mL 10% ethyl acetate/dichloromethane).
• the fractions containing product are concentrated and hexane is added to the solution to precipitate out the product affording 23.7 g (70.2% yield) of racemic ⁇ 1-methyl-2-[7-cyanomethoxy-1H-indol-3-yl]ethyl ⁇ -carbamic acid tert-butyl ester.
• Amine 8b is prepared from (S)- ⁇ 1-methyl-2-[7-cyanomethoxy-1H-indol-3-yl]ethyl ⁇ -carbamic acid tert-butyl ester by a procedure substantially similar to that described for amine 8a.
• Amine 11 is prepared according to the literature procedure detailed in J. Med. Chem., 23:285–289, 1980.
• the title amines are prepared from [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester and 2-chloro-isonicotinonitrile and [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester and 6-chloro-nicotinonitrile, respectively, as described for the preparation of Amine 12.
• the title amine is prepared from Boc-D-alanine (5 g, 24.4 mmol) and indoline (3.2 ml, 29 mmol) by a procedure substantially similar to that described above for Amine 20.
• Trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester 200 mg, 0.46 mmol
• methyl acrylate 80 mg, 0.92 mmol
• triethylamine 0.40 mL, 3.0 mmol
• Dichlorobis(triphenylphosphine)palladium 31 mg, 0.045 mmol
• 3-[3-(2-tert-Butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-propionic acid methyl ester is prepared from 3-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-acrylic acid methyl ester as described below for the preparation of ⁇ 2-[7-(2-methanesulfonyl-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl ⁇ -carbamic acid tert-butyl ester (80%).
• FDMS m/e 375.2 (M + +1).
• the title amine is prepared from 3-[3-(2-tert-Butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-propionic acid methyl ester as described for the alternate preparation of Amine 6 (100%).
• the title amine is prepared from ⁇ 2-[7-(2-methanesulfonyl-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl ⁇ -carbamic acid tert-butyl ester as described for the alternate preparation of Amine 6 (80%).
• FDMS m/e 293.2 (M + +1).
• the title amine is prepared from ⁇ 2-[7-(2-methanesulfonyl-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl ⁇ -carbamic acid tert-butyl ester as described for the alternate preparation of Amine 6 (92%).
• FDMS m/e 295.2 (M + +1).
• the title amine is prepared from ⁇ 2-[7-(2-Cyano-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl ⁇ -carbamic acid tert-butyl ester as described for the alternate preparation of Amine 6 (94%).
• FDMS m/e 240.2 (M + +1).
• ⁇ 2-[7-(2-Cyano-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl ⁇ -carbamic acid tert-butyl ester is prepared from ⁇ 2-[7-(2-cyano-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl ⁇ -carbamic acid tert-butyl ester as described for the preparation of Amine 28 (86%).
• FDMS m/e 341.2 (M + +1).
• the title amine is prepared from ⁇ 2-[7-(2-Cyano-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl ⁇ -carbamic acid tert-butyl ester as described for the alternate preparation of Amine 6 (86%).
• FDMS m/e 242.2 (M + +1).
• ⁇ 1,1-Dimethyl-2-[7-(2-[1,2,4]triazol-1-yl-vinyl)-1H-indol-3-yl]-ethyl ⁇ -carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and 1-vinyl-1,2,4-triazole as described for the preparation of Amine 23 (93%).
• FDMS m/e 381.2 (M + +1).
• 2-bromo-4,6-difluoro-N-carbethoxy aniline (42 g, 150 mmol) in CH 3 CN (500 mL) is degassed with vacuum and purged with N 2 .
• Dichlorobis(triphenylphosphine)palladium(II) (10.5 g, 15 mmol, 10 mol %), followed by CuI (710 mg, 4 mmol, 2.5 mol %) and triethyl amine (41 mL) are added and rinsed in with 100 mL of CH 3 CN.
• Trimethylsilyl acetylene (31.8 ml, 225 mmol) is added and reaction is refluxed under N 2 .
• Fresh sodium ethoxide is prepared by carefully adding NaH (16 g of 60% oil dispersion, 400 mmol) to 550 mL of ethanol under N 2 .
• 2-(Trimethylsilylethynyl)-4,6-difluoro-N-carbethoxyaniline (28 g, 100 mmol) in 150 mL of ethanol is added and reaction is stirred at room temperature approximately 45 minutes, while monitoring by TLC (20% ethyl acetate/hexane, UV) until all the starting material is consumed. The mixture is heated to reflux and monitored by TLC until the intermediate material is consumed (approx. 1 hour).
• Lithium aluminum hydride (LAH) (0.7 g, 18 mmol) is added portionwise to a dioxane/tetrahydrofuran (90 ml/10 ml) solution of 2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol (1.9 g, 3.3 mmol) under N 2 at 0° C. After the addition is complete, the reaction is allowed to warm to room temperature, then is refluxed for 1 hour.
• LAH Lithium aluminum hydride
• reaction is quenched with H 2 O and 15% aqueous NaOH, filtered, and the filtrate is diluted with ethyl acetate, washed with brine, dried (Na 2 SO 4 ), filtered, concentrated, and the residue is purified by flash chromatography (SiO 2 , ethyl acetate/hexane gradient) to yield 1.2 g of dibenzyl-[2-(5,7-difluoro-1H-indol-3-yl)-1(S)-methyl-ethyl]-amine (86%).
• the title amine is prepared from N-benzenesulfonyl-3-iodo-5,7-difluoro-indole and (R) N,N dibenzyl-2-aminopropanal by a procedure substantially similar to that described for Amine 34.
• reaction is quenched with cold aqueous NaHCO 3 , xtracted with ethyl acetate, washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and is purified by flash chromatography (SiO 2 , ethyl acetate/hexane gradient) to yield 1.3 g of dibenzyl-[2-(5,7-difluoro-1-methyl-1H-indol-3-yl)-1(R)-methyl-ethyl]-amine (89%).
• the title amines are prepared from 5-hydroxyindole, 4-hydroxy-2-methylindole, indole and 6-hydroxyindole, respectively, substantially as described for Amine 39.
• Amine 50 is prepared from 5-fluoro-3-(dimethylaminomethyl)-1H-indole in a method similar to that described for the preparation of Amine 49.
• Methyl indole-4-carboxylate (7.0 g, 40 mmol) and Eschenmoser's salt (N,N-dimethylnethyleneammonium iodide; 7.8 g, 42 mmol) are combined in 130 ml of acetic acid. After heating at 65° C. for 2 hours, the reaction mixture is concentrated in vacuo. The resulting solid is triturated with ethyl acetate, filtered and dried in vacuo to give 3-dimethylaminomethyl-1H-indole-4-carboxylic acid methyl ester hydroiodide in quantitative yield.
• 6-Fluoro-3-(2-methyl-2-nitropropyl)-1H-indole is prepared from 6-fluoro-3-(dimethylaminomethyl)-1H-indole by a method similar to that described for Amine 49, paragraph 1.
• 6-Benzyloxyindole-3-carboxaldehyde is converted to 2-(6-benzyloxy-1H-indoyl-3-yl)-1,1-dimethylethylamine by sequentially following the procedures detailed for Amine 61, 1 st paragraph, then for Amine 57, 1 st and 2 nd paragraphs.
• the BOC protected amine is deprotected substantially as described for Amine 6 to give the title amine 58 in 66% yield.
• the title amine is prepared from 5-benzyloxy-3-(dimethylaminomethyl)-1H-indole by following the procedures detailed for Amine 57, 1 st and 2 nd paragraphs, followed by the methods described for Amine 58, 2 nd–4 th paragraphs.
• Amine 60 is prepared from 7-fluoroindole by sequentially following the methods described for Amine 51, 1 st paragraph; Amine 49, 1 st paragraph; and Amine 51, 3 rd paragraph.
• the title amines are prepared from methyl indole-5-carboxylate, 5-cyanoindole, methyl indole-7-carboxylate, 6-cyanoindole and 4-cyanoindole, respectively, in a method similar to that described for the preparation of Amine 51.
• Amine 63 is prepared from Amine 62 in 61% yield by essentially following the procedure described for Amine 53.
• the title amine is prepared from [2-(7-(methanesulfonamidylcarbomethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester as described for the preparation of Amine 1 (108 mg, 70%).
• the title amines are prepared from trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester and: 4-methoxycarbonylbenzeneboronic acid; 4-acetamidylbenzeneboronic acid; 3-methoxycarbonylbenzeboronic acid; and 5-methoxycaronylthiophen-2-ylboronic acid, respectively, using the procedure described for the preparation of Amine 2.
• ⁇ 1,1-Dimethyl-2-[7-(2-pyrazin-2-yl-vinyl)-1H-indol-3-yl]-ethyl ⁇ -carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and 2-vinylpyrazine as described for the preparation of Amine 23 (99%).
• FDMS m/e 393.2 (M + +1)
• the title amine is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and p-sulfonamido styrene as described for the preparation of Amine 23 (70%).
• FDMS m/e 370.2 (M + +1).
• Trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-6-yl ester is prepared from 6-benzyloxy gramine and 2-nitropropane as described in the preparation of Amine 1, 1 st–5 th paragraphs.
• Trifluoromethanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-6-yl ester and acrylonitrile are reacted and the Boc-protecting group is removed from the resulting product as described in the prepararation of Amine 23 to give the title amine (75%).
• FDMS m/e 240.2 (M + +1).
• the 7-nitrogramine salt (2.0 g, 5.8 mmol) is suspended in a mixture of 2-nitropropane (9.5 mL) and methanol (9.5 mL). Dimethylsulfate (1.09 mL, 11.5 mmol) is added dropwise via syringe, and the resulting yellow solution is stirred at room temperature for 5 minutes. Sodium methoxide (0.62 g, 11.5 mmol) is then added in one portion, and the mixture is stirred overnight at room temperature. The reaction is quenched by addition of saturated NH 4 Cl solution and ethyl acetate.
• 3-(2-Nitro-2-methylpropyl)-7-nitroindole (1.89 g, 7.2 mmol) is dissolved in ethyl acetate (75 mL) and 10% Pd/C is added (750 mg). The mixture is stirred under a balloon of nitrogen for 2–3 hours. The mixture is filtered to remove the Pd/C, and the filtrate is evaporated to give a crude oil. This crude 3-(2-nitro-2-methylpropyl)-7-aminoindole is immediately dissolved in pyridine (100 mL) and the solution is cooled with an ice bath to 0° C.
• Benzenesulfonyl chloride is added slowly, and the mixture is stirred for 5 minutes at this temperature before removing the ice bath.
• the reaction mixture is stirred overnight before being quenched by addition of 1N HCl and ethyl acetate.
• the aqueous layer is extracted with ethyl acetate several times and the combined organic extracts are washed twice with brine and dried over Na 2 SO 4 to give a crude oil.
• the crude material is purified by flash chromatography (25% ethyl acetate/hexanes) to provide 1.9 g of 3-(2-nitro-2-methylpropyl)-7-benzenesulfonamidyl-indole (71%).
• 3-(2-Nitro-2-methylpropyl)-7-methanesulfonamidyl-indole is prepared from crude 3-(2-nitro-2-methylpropyl)-7-aminoindole and methanesulfonyl chloride and 3-(2-nitro-2-methylpropyl)-7-methanesulfonamidyl-indole is converted to the title amine by the procedure described for Amine 77 (2.3 g).
• Boc-protected title amine is prepared from Boc- ⁇ -methylalanine and indoline by the procedure described above for Amine 20 except that the reaction is conducted in dichloromethane and the crude Boc-protected amine is purified by normal phase flash chromatography (silica gel, 20–60% ethyl acetate/hexanes).
• the mixture is cooled to room temperature, and trifluoro-methansulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (0.8 equivalents), 1,1′-bis(diphenylphosphino) ferrocene)palladium(II)dichloride-dichlormethane (0.03 equivalents) and 2M Na 2 CO 3 (5 equivalents) are added under argon. The resulting mixture is heated to 80° C. and then allowed to stir overnight at this temperature. The mixture is diluted with water and extracted with ethyl acetate or CH 2 Cl 2 .
• the Boc-protected amine is dissolved in 5N HCl in isopropanol (5 ml/mmol) and stirred overnight at room temperature. The mixture is evaporated, dissolved in ethanol and loaded onto a 5 g SCX column conditioned with methanol. The column is washed twice with 5 ml ethanol to remove impurities. The title compound is then eluted with 5 ml ethanolic NH 3 and 5 ml ethanol. Evaporation of the solvent gives the deprotected amine.
• the title amines are prepared from trifluoro-methansulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester and: ethyl 3-bromobenzoate; 3′-bromoacetophenone; and 4′-bromoacetophenone, respectively, using the procedure described for the preparation of Amine 81.
• Amine 85 is prepared by hydrolysis of the methyl ester of Amine 62 by essentially following the procedure detailed for Amine 86.
• Amine 88 is prepared from indole-2-carboxylic acid and 1,2-diamino-2-methylpropane by essentially following the procedure detailed for Amine 55.
• the title compound is prepared from Epoxide 31 and Amine 6 as described above for Aryl Halide 1.
• the title compound is prepared from Epoxide 31 and Amine 11 as described above for Aryl Halide 1.
• a vial is charged with a solution of single amine of formula III (0.2M in ethanol or t-butanol, 90 micromolar) and a solution of a single epoxide of formula II (0.2M in dimethylsulfoxide, 80 micromolar).
• the vial is sealed and heated to 80° C. for 24–48 hours.
• the solution is cooled to room temperature, diluted with methanol, and passed over a cation exchange column, eluting the basic material with 1N methanolic ammonia.
• a stirred mixture of an epoxide of formula II (1 equivalent) and an amine of formula II (1–2 equivalents) in ethanol, methanol, n-butanol or t-butanol is heated at 70–80° C. for 2–72 hours.
• the solvent is evaporated to dryness to give a crude oil that is optionally diluted with methanol or ethanol and passed over a cation exchange column (eluting the free base product with 1N methanolic ammonia) before further purification.
• the final products prepared via Representative Procedure 1 or 2 may be further purified by flash or radial chromatography.
• Typical chromatography conditions include: a) using a variable mixture of 25:5:1 chloroform/methanol/ammonium hydroxide and 9:1 chloroform/methanol; b) a variable mixture of 90:10:1 CH 2 Cl 2 /ethanolic NH 3 gradient; c) dichloromethane/6–12% methanol, 0.15–0.35M ammonia in dichloromethane gradient; d) methylene chloride with a step gradient to 2–8% methanol; e) chloroform/2.0M ammonia in methanol, from 0–10% to 6–20% gradient elution or f) isocratic 6–8% 2M ammonia in methanol: 92–94% dichloromethane.
• the final products may be purified on C18 bonded silica gel using either mass guided or UV guided reverse phase liquid chromatography (acetonitrile/water with 0.01% hydrochloric acid or 0.1% trifluoroacetic acid).
• the free base thus prepared may be salified, e.g., by dissolution of the free base in CH 2 Cl 2 or diethylether, adding 1M ethanolic HCl or a solution of HCl in diethylether, and evaporating the volatiles, or as described in more detail below.
• a hydrochloride salt may be prepared by dissolving the free base in dichloromethane, diethylether, or a mixture of ethyl acetate and methanol and adding 1M ethanolic HCl, a solution of HCl in diethylether, or 0.5M ammonium chloride. The resultng mixture is allowed to stir for a short time, e.g., for five minutes, before evaporating the volatiles and optionally triturating in diethyl ether to give the hydrochloride salt.
• the oxalate salts may be prepared by dissolving the free base in a small amount of ethyl acetate, optionally adding methanol for solubitity. The resulting solution is treated with 1 equivalent of a 0.5M solution of oxalic acid in ethyl acetate. The reaction mixture is either concentrated in vacuo or centrifuged, separated, and the solids are dried, to give the oxalate salt.
• the free base may be dissolved in a small amount of ethyl acetate or methanol and then treated with 1 equivalent of succinic acid in methanol.
• the resulting slurry is dissolved in the minimum amount of methanol then concentrated in vacuo to give the succinate salt.
• Amine 6 (12.08 g, 43.2 mmol, 1.10 equivalents) is dissolved in acetonitrile (86 mL) containing N-(trimethylsilyl)acetamide (95% pure, 5.1 g, 39.2 mmol, 1.0 equivalent—warmed to effect dissolution).
• Epoxide 3 is then added (8.0 g, 96% pure, 1.0 equivalent) and the solution is allowed to stand at 24–26° C. for 45 hours after which water (10 mL) and acetic acid (6.3 g) are added. After 1.5 hours, the bulk of the solvents are removed under vacuum (25° C., 10 mm, 16 hours).
• Epoxide 1 (232 mg, 1 mmol), Amine 33 (255 mg, 1.1 mmol), and ytterbium trifluoromethane sulfonate hydrate (62 mg, 0.1 mmol) in 10 ml acetonitrile are reacted and purified as in Example 194 to give 92 mg of the free base of the title compound (20%).
• a 5 ml methanol solution of the free base (92 mg, 0.2 mmol) and NH 4 Cl (11 mg, 0.2 mmol) is stirred for 5 minutes at room temperature, concentrated, triturated in diethylether, filtered, and dried to give 95 mg of the title compound.
• the free base is dissolved in a small amount of ethyl acetate, optionally adding methanol for solubitity.
• the resulting solution is treated with 1 equivalent of a 0.5M solution of oxalic acid in ethyl acetate.
• the reaction mixture is either concentrated in vacuo or centrifuged, separated, and the solids are dried, to give the title compound.
• Racemic Amine 45 and Epoxide 1 are coupled in a fashion similar to that described in Representative Procedure 2 to give a mixture of the free bases of the title compounds.
• the title compounds are separated, one from the other, by normal phase chiral HPLC (Chiralpak AD; 15% 3A ethanol in heptane with 0.2% dimethylethylamine) to give the free base of Example 200 (faster eluting) in 40% yield and the free base of Example 201 in 35% yield.
• the oxalate salts are prepared by separately dissolving each of the free base isomers in a small amount of ethyl acetate, optionally adding methanol for solubility.
• Epoxide 3 is reacted with Amine 7 according to the Representative Procedure 2.
• the crude amination mixture (290 mg) is dissolved in 10 ml ethanol, 2M NaOH (2 ml) is added and the resulting mixture is left to stir at room temperature overnight.
• the solution is neutralized with acetic acid and loaded on a SCX column. After washing with ethanol, the product is eluted with 10% NH 3 in ethanol. The fractions containing product are combined and evaporated to yield 220 mg of the title compound (80%).
• Emax (SEM) 73.8 (8.0).
• a compound of formula V (6.4 mmol) is dissolved in 50 ml of dry dioxane and thoroughly flushed with argon. Palladium(0) tetrakis(triphenylphosphine) (750 mg, 0.64 mmol) is added under argon and stirred at ambient temperature until the mixture becomes homogenous. The clear solution is divided into aliquots of 2 ml, and each testing tube is charged with 2 equivalents of an aryl boronic acid and 500 microliters of 2M aqueous sodium carbonate under argon. The testing tubes are sealed and heated in a microwave oven (MLS ETHOS 1600) for 35 minutes and 100° C. at 1000 W.
• MLS ETHOS 1600 microwave oven
• the final products prepared via Suzuki coupling may be purified by normal phase chromatography (silica gel, dichloromethane/ethanolic ammonia) providing the free bases or by reverse phase chromatography (acetonitrile/0.1% trifluoroacetic acid or 0.01% HCl in water) providing the trifluoro acetate or hydrochloride salts.
• the final products existing as salts may also be prepared in a separate salification step by dissolution of the free base in ethanol or dichloromethane and treatment of the solution with acid, e.g., 1N ethanolic HCl. Removal of all volatiles under reduced pressure, affords the desired salt.
• Potassium carbonate 14 mg is added to 2 mL of dimethylsulfoxide.
• the mixture is stirred under nitrogen, and heated to 50° C. for 30 minutes.
• the mixture is cooled to room temperature, and the compound of Example 115 (27 mg) dissolved in 2 mL of dimethylsulfoxide is added to the mixture, followed by the addition of 0.5 mL of water dropwise.
• the mixture is allowed to stir for 10 to 15 minutes, then 0.1 mL of 30% hydrogen peroxide is added dropwise. After 20 minutes, 15 mL of saturated aqueous sodium sulfite solution and 5 ml water is added and the mixture is extracted 3 times with 40 mL of ethyl acetate.
• the title compound is prepared from the compound of Example 137 (200 mg, 0.43 mmol) by a procedure substantially similar to that described for Example 223 to give 50 mg of the title compound (85%).
• FDMS m/e 495.2 (M + +1).
• the free base of the title compound is prepared from the compound of Example 143 (76 mg, 0.16 mmol) and azidotrimethylsilane (190 mg, 1.62 mmol) by a procedure substantially analogous to that described in Example 229 to give the title compound.
• FDMS m/e 515.2 (M + +1).
• the title compound is prepared from the compound of Example 144 and azidotrimethylsilane by a procedure substantially analogous to that described in Example 229 to give the title compound.
• FDMS m/e 517.2 (M + +1).
• the title compounds are separately prepared from the compound of Examples 24, 151, 168 and 169, respectively, in a manner similar to that described in Example 233.
• the title compounds are separately prepared by hydrolysis of crude free base of the product from Examples 70, 75 and 76, respectively, in a method similar to that detailed in Example 238.
• the title compound is prepared in 54% yield by hydrolysis of the free base of the compound of Example 154 with LiOH in a manner similar to that described in Example 242.
• Example 116 The compound of Example 116 (97 mg) is dissolved in 6 mL of methanol. Sodium hydroxide (2N, 3 mL) is added and the mixture is refluxed for 16 hours. Water (10 ml) is added and the pH of the mixture is adjusted to 3 using 1N hydrochloric acid. The aqueous mixture is extracted with ethyl acetate (3 ⁇ 50 mL). The combined organic extracts are dried with anhydrous sodium sulfate, filtered, and the solvent is evaporated.
• the crude title compound is prepared from he compound of Example 116 (97 mg) via the procedure described in Example 219.
• FDMS m/e 542 (M + +1 of free base).
• Example 182 The compound of Example 182 is converted to the title compound via the procedure described for the preparation of the compound of Example 246 (57%).
• FDMS m/e 526 (M + +1 of free base).
• Example 180 is converted to the title compound via the procedure described for the preparation of the compound of Example 246 (88%).
• FDMS m/e 541 (M + +1 of free base).
• Example 184 The compound of Example 184 is converted to the title compound via the procedure described for the preparation of the compound of Example 246 (32%).
• FDMS m/e 526 (M + +1 of free base).
• Example 2 The compound of Example 1 (8.87 g, 18.8 g, 1.00 equivalent) is treated all at once with concentrated HCl (1.57 mL, 0.95 equivalents) in ethyl acetate (221 mL, 25° C.). The ethyl acetate is evaporated under vacuum and the solid stirred with 250 mL of diethyl ether (3 hours) after which the mixture is filtered and the resulting solid dried under a stream of nitrogen to afford 8.98 g of the title compound (93%). MS: 459.2.
• Example 216 To solution of the compound of Example 216 in dry ethanol is added 10% HCl in ethanol and the mixture is stirred at room temperature. The solvent is evaporated, the residue re-dissolved in ethanol and loaded on a SCX column. After washing with ethanol, the products are eluted with 10% NH 3 in ethanol, evaporated, separated and purified via preparative HPLC (C18 bonded silica gel reverse phase liquid chromatography (acetonitrile/water with 0.1% trifluoroacetic acid) to give the title compounds.
• preparative HPLC C18 bonded silica gel reverse phase liquid chromatography (acetonitrile/water with 0.1% trifluoroacetic acid) to give the title compounds.
• Cells from each of the above cell lines are resuspended and added (20,000/well) to a 96-well plate. Cells are incubated at 37° C. with representative compounds of the invention for 20 minutes in buffer (Hank's balanced salt solution, 10 mM HEPES, 0.1% BSA, 1 mM L-ascorbic acid, 0.2% dimethyl sulfoxide, 1 mM 3-isobutyl-1-methylxanthine, pH 7.4).
• buffer Hort's balanced salt solution, 10 mM HEPES, 0.1% BSA, 1 mM L-ascorbic acid, 0.2% dimethyl sulfoxide, 1 mM 3-isobutyl-1-methylxanthine, pH 7.4
• c-AMP level is quantified by scintillation proximity assay (SPA) using a modification of the commercially available c-AMP kit (Amersham, Arlington Heights, Ill.) with rabbit anti-cAMP antibody (ICN Biomedicals, Aurora, Ohio) for the kit.
• quench buffer 50 mM Na Acetate, 0.25% Triton X-100, pH 5.8
• SPA scintillation proximity assay
• Isoproterenol is accepted in the art as a non-selective ⁇ 3 agonist and is widely used as a comparator in evaluating the activity of compounds. See Trends in Pharm. Sci., 15:3, 1994.
• the % intrinsic activity (Emax) of representative compounds of the invention is assessed relative to isoproterenol by the compound's maximal response divided by the isoproterenol maximal response times 100.
• the salts of the present invention are useful in treating conditions in human and non-human animals in which the ⁇ 3 receptor has been demonstrated to play a role.
• the diseases, disorders or conditions for which compounds of the present invention are useful in treating include, but are not limited to, (1) diabetes mellitus, (2) hyperglycemia, (3) obesity, (4) hyperlipidemia, (5) hypertriglyceridemia, (6) hypercholesterolemia, (7) atherosclerosis of coronary, cerebrovascular and peripheral arteries, (8) hypertension, (9) disorders of the gall bladder including acute and chronic cholecystitis, (10) depression, (11) elevated intra-ocular pressure and glaucoma, (12) non-specific diarrhea dumping syndrome, (13) hepatic steatosis [fatty degeneration of the liver], and obesity dependent diseases/disorders such as: (14) gastrointestinal disorders including peptid ulcer, esophagitis, gastritis and duodenitis, (including that induced by H.
• intestinal ulcerations including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis and gastrointestinal ulcerations
• irritable bowel syndrome and other disorders needing decreased gut motility (16) diabetic retinopathy, (17) neuropathic bladder dysfunction, (18) osteoarthritis, (19) restrictive lung disease, (20) obstructive sleep apnea, (21) congestive heart failure, (22) venous stasis and skin disorders related to venous stasis, (23) decreased libido (in both males and females), and (24) acute and chronic cystitis.
• obesity dependent means that the symptoms of said diseases will be ameliorated via the present salt's effect on the patient's weight.
• BMI body mass index
• a patient population at particular need of treatment are those with a BMI>30 or >27 with co-morbities.
• Human patients in need of type 2 diabetes treatment are typically individuals with a BMI ⁇ 25, i.e., individuals that are not overweight.
• the compound of formula I is preferably formulated in a unit dosage form prior to administration. Therefore, yet another embodiment of the present invention is a pharmaceutical formulation comprising a compound of formula I and a pharmaceutical carrier.
• the active ingredient (formula I compound) will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
• a carrier which may be in the form of a capsule, sachet, paper or other container.
• the carrier serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
• compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
• Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
• the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
• the compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
• FORMULATION 1 Tablets Ingredient Quantity (mg/tablet) Active Ingredient 5–500 Cellulose, microcrystalline 200–650 Silicon dioxide, fumed 10–650 Stearate acid 5–15 The components are blended and compressed to form tablets.
• Intravenous Solution Ingredient Quantity Active Ingredient 25 mg Isotonic saline 1,000 ml The solution of the above ingredients is intravenously administered to a patient at a rate of about 1 ml per minute. Dose
• the specific dose administered is determined by the particular circumstances surrounding each situation. These circumstances include, the route of administration, the prior medical history of the recipient, the pathological condition or symptom being treated, the severity of the condition/symptom being treated, and the age and sex of the recipient. However, it will be understood that the therapeutic dosage administered will be determined by the physician in the light of the relevant circumstances.
• an effective minimum daily dose of a compound of formula I is about 5, 10, 15, or 20 mg.
• an effective maximum dose is about 500, 100, 60, 50, or 40 mg. Most typically, the dose ranges between 15 mg and 60 mg.
• the exact dose may be determined, in accordance with the standard practice in the medical arts of “dose titrating” the recipient; that is, initially administering a low dose of the compound, and gradually increasing the does until the desired therapeutic effect is observed.
• the compounds can be administered by a variety of routes including the oral, rectal, transdermal, subcutaneous, topical, intravenous, intramuscular or intranasal routes.
• the compound of formula I may be used in combination with other drugs that are used in the treatment of the diseases or conditions for which the present salts are useful, e.g., treatment of obesity and/or type 2 diabetes.
• Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
• a pharmaceutical unit dosage form containing such other drugs in addition to the present salt is preferred.
• the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

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